Next-Generation Immunotherapy Platforms

Multi-Model Immunotherapy and Cell Therapy Platforms that Create a ‘Cancer BioShield’

The immune system is a collection of diverse cell families, each with a distinct role in protecting us from infections and disease. Among these are natural killer (NK) cells, the body’s first line of defense. As part of the innate immune response, NK cells can recognize and destroy abnormal cells (such as cancerous or virally infected cells) immediately, without prior sensitization. We harness this power with our activated NK (aNK) cell platform, based on a unique NK cell line that is highly cytotoxic. A further engineered version of these aNK cells, PD-L1 targeted high-affinity NK (PD-L1 t-haNK) cells, are even more effective and overcome deficits in immune function. By deploying ready-to-act NK cells, we aim to provide an immediate immune assault on tumor cells.

To further amplify the innate immune attack, we have developed a proprietary interleukin-15 agonist called ANKTIVA® (nogapendekin alfa inbakicept, NAI; also known as N-803). This IL-15 receptor agonist complex selectively stimulates the proliferation of NK cells and CD8 + “memory” T cells, without expanding the suppressive regulatory T cells that could dampen anti-tumor responses. ANKTIVA can repeatedly boost the immune system without the safety challenges observed with high-dose IL-2 therapies. In essence, ANKTIVA ignites a coordinated triangle offense of NK cells alongside CD8+ CD4+ T cells, driving robust immune activation and long-lived memory T cell responses that can be described as a ‘Cancer BioShield.’

Clinical Synergy and Durable Responses

ANKTIVA can be combined with other therapies for clinical synergy, and this approach has produced impressive immune responses in difficult-to-treat cancers. Notably, the combination of intravesical N-803 (ANKTIVA) plus BCG therapy has elicited durable complete responses in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS). In a pivotal phase 2/3 trial (QUILT 3.032) for patients with high-risk BCG-unresponsive NMIBC CIS, 71% of patients achieved a complete response with ANKTIVA plus BCG. This translated to a greater than 90% bladder preservation rate at two years, meaning the vast majority of responders avoided a life-altering cystectomy.

The durability of responses with ANKTIVA is striking – many responders remain cancer-free beyond three years of follow-up. At the 36-month update of QUILT 3.032, among patients who achieved a complete response, 84% were still free from cystectomy at three years, with a disease-specific survival of ~99%. “This represents the highest bladder-sparing rate to date in BCG-unresponsive disease,” noted Dr. Sam Chang, a leading urologic oncologist and QUILT 3.032 study investigator, underscoring the potential of IL-15-based therapy to transform NMIBC CIS management. These positive outcomes formed the basis for FDA approval of ANKTIVA in April 2024 as the first-in-class IL-15 immunotherapy for BCG-unresponsive NMIBC CIS. Just weeks after approval, the first commercial doses reached patients, marking a new immunotherapy option for urologists and their NMIBC CIS patients seeking alternatives to bladder removal.

Beyond bladder cancer, ANKTIVA is showing promise in restoring immune responsiveness in other malignancies. ANKTIVA’s unique mechanism of action – proliferating NK and T cells and restoring antigen presentation – can rescue anti-tumor immunity in patients who have failed other therapies. For example, in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on checkpoint inhibitors, adding ANKTIVA has led to prolonged survival compared to expected outcomes. In a Phase 2 study (QUILT 3.055), the combination of N-803 with a PD-1 checkpoint inhibitor achieved median overall survival times on the order of 14-19 months in refractory NSCLC, exceeding historical survival after chemotherapy in this setting. These results that reflect ANKTIVA’s ability to effectively rescue T cells and checkpoint therapy efficacy – have spurred a new randomized Phase 3 trial in NSCLC in collaboration with BeiGene to confirm the benefit of ANKTIVA plus PD-1 blockade. Notably, ANKTIVA is the first FDA-approved therapy shown to increase circulating lymphocytes via IL-15 stimulation. This lymphocyte-proliferative effect is now being leveraged in clinical strategies to counteract cancer-associated immunosuppression.

Protecting the Immune System and Reversing Lymphopenia

Many standard cancer treatments – chemotherapy, radiation, CAR-T cell therapy, and even prolonged checkpoint inhibitor use – can cause lymphopenia, a drastic reduction in the patient’s lymphocyte counts. Treatment-induced lymphopenia is associated with worse clinical outcomes and leaves patients vulnerable to infections and relapse. Currently, no approved therapy specifically addresses this loss of immune cells. ANKTIVA’s IL-15 agonist activity offers a novel way to replenish and expand lymphocyte populations during or after these treatments, effectively serving as an immune ‘BioShield.” In fact, the FDA granted ANKTIVA a Regenerative Medicine Advanced Therapy (RMAT) designation in 2025 for the prevention or reversal of therapy-induced lymphopenia. We have opened an Expanded Access Protocol to make ANKTIVA available as a supportive care adjunct for patients experiencing severe lymphopenia from cancer or cancer therapy.

Innovating the Immunotherapy Landscape

Our platforms that are elements of the Cancer BioShield are built on the foundation of complementary immune-modulating technologies – from cytokine fusion proteins like ANKTIVA, to cell therapies like PD-L1 t-haNK and cancer-specific vaccines – that can be combined for greater effect. Our clinical pipeline reflects this breadth, with trials spanning bladder, lung, ovarian, and other cancers as well as viral infections such as HPV. As we continue to advance late-stage trials in multiple indications, we remain focused on rigorous science and patient outcomes. Each program is informed by deepening insight into immunology – whether it’s enhancing trained immunity in the bladder with IL-15 or overcoming T cell exhaustion in the lung by rescuing MHC-I presentation.

Our next-generation immunotherapy platforms engage both arms of the immune system to fight cancer: Natural killer cells and IL-15 agonists to provide a powerful one-two punch to jump-start innate immunity and expand T cell populations. By integrating these approaches, we strive to achieve a higher rate of and more durable remissions for patients across a wide range of cancers, living up to the promise of a Cancer BioShield. Ongoing clinical trials and a recent FDA approval underscores the potential of this strategy to usher in a new era of immunotherapy – one beyond checkpoints, where the immune system’s full arsenal (NK cells, T cells, and immunological memory) is engaged in the fight against cancer.

References

1. Boyman, O., & Sprent, J. (2012). The role of interlekin-2 during homeostasis and activation of the immune system. Nature Reviews Immunology, 12(3).

2. Waldmann, T.A. (2018). The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunology Research.

3. Addeo, R., et al. (2024). ANKTIVA plus BCG in BCG-unresponsive NMIBC: Updated 3-year data from QUILT 3.032. AUA Annual Meeting 2024 Presentation.

4. Chang, S.S. (2024). Oral commentary on QUILT 3.032 at AUA.

5. ImmunityBio Press Release. (April 2024). FDA Approves ANKTIVA for BCG-Unresponsive NMIBC.

6. Balar, A.V., et al. (2017). Phase II study of pembrolizumab in BCG-unresponsive NMIBC. J Clin Oncol.

7. FDA. (April 22, 2024). ANKTIVA approval announcement.

8. Patel, J.D., et al. (2023). Safety and efficacy of ANKTIVA plus checkpoint inhibitor in advanced NSCLC. ASCO Annual Meeting Abstracts.

9. ImmunityBio & BeiGene. (2024). Joint press release – initiation of Phase 3 trial in NSCLC.

10. Mackall, C.L., et al. (2011). Lymphopenia and cancer therapy. Nature Reviews Cancer.

11. ImmunityBio. (2025). Expanded Access Protocol for treatment-related lymphopenia.